This application, entitled 'The Role of Rare Variants in Multiple Sclerosis Risk', addresses Research and Research Infrastructure 'Grand Opportunities'. Many human autoimmune diseases, including multiple sclerosis (MS) are complex genetic disorders. MS is an inflammatory disease of the central nervous system white matter. The unbiased approach of studying the entire human genome for risk alleles has led to the identification of common allelic variants that are associated with risk to developing MS. A major short-coming of current high-throughput genotyping platforms and study designs is that only genetic variants that have a relatively high frequency in the population have been assessed (and discovered) in MS risk to date. This conclusion is supported by the observation that all of the validated alleles implicated in risk to MS have minor allele frequency (MAF) >0.10 in the populations of European ancestry in which the association studies have been performed. However, recent evidence suggests that rare variants may represent critical components of the allelic architecture of common autoimmune diseases, including Crohn's disease and type 1 diabetes. To assess the role of rare allelic variants in MS risk, we will perform a high-throughput sequencing experiment using Illumina's Solexa technology. Subsequently, we will validate these variants by genotyping a large collection of MS cases and controls. As we have strong evidence that MS shares common risk alleles with Crohn's disease, we will also genotype a set of rare variants discovered in CD cases in our collection of MS cases and controls to assess the commonalities between the two autoimmune diseases. This project will 1) provide a catalogue of rare variants in genomic regions implicated in MS susceptibility, 2) discover novel variants implicated in MS and CD risk, and 3) pin- point towards disease-causing mechanisms. PUBLIC HEALTH RELEVANCE: Title: The Role of Rare Variants in Multiple Sclerosis Risk Narrative - The recent successes of genome wide association scans have provided a growing list of allelic variants implicated in the risk of common human diseases. A major short-coming of current genome-wide genotyping platforms and study designs is that only genetic variants that have a relatively high frequency in the population have been assessed and discovered in multiple sclerosis (MS) risk to date. Using high-throughput sequencing and genotyping technologies to study the largest DNA collection of multiple sclerosis and controls available, this project will 1) provide a catalogue of rare variants in genomic regions implicated in MS susceptibility, 2) discover novel variants implicated in risk of developing MS and other autoimmune diseases, and 3) pin-point towards disease-causing mechanisms.